tbuckley/cabot-search huggingface dataset:
<sup>18</sup>F-MFBG PET imaging in patients with neuroblastoma: Lesion targeting and comparison with MIBG.
Authors: Shakeel Modak, Audrey Mauguen, Ellen M. Basu, Anita Price, Gerald Behr, Ryan Min, Serge K. Lyashchenko, Jazmin Schwartz, Neeta Pandit-Taskar
Journal: Journal of Clinical Oncology (2023)

10046 Background: 123 I-MIBG gamma camera imaging (MIBG) is routinely used for the imaging of neuroblastoma. Limitations include need for two-day imaging schedule and lack of quantitative uptake measurements. Phase I study showed that 18 F-MFBG (MFBG), a positron-emitting analog of MIBG, is safe and feasible (PMID:28705916). In the follow-up phase II trial (NCT02348749) we evaluated MFBG PET imaging, comparing neuroblastoma lesion between the two modalities. Methods: Patients with known neuroblastoma underwent whole- body PET CT or PET-MR imaging one hour post-injection with 8mCi/1.7m2 of MFBG. All patients had concurrent MIBG scan with planar and SPECT-CT imaging without intervening therapy. MFBG and MIBG images were independently analyzed for lesion targeting; lesion number, site and uptake was noted for each patient and compared. Discordant lesions were further investigated with correlative imaging and/or clinical follow up. MFBG score was generated, similar to the modified Curie score for MIBG, for each patient. Results: 25 patients (median age 8 y) underwent MFBG scans at a median of 2 (range 0-24) days after MIBG scans; in one patient MFBG scan was performed 1 day before MIBG scan. No MFBG-related adverse events were noted. 24 patients had both MIBG and MFBG positive scans while 1 patient had both MIBG and MFBG negative scans. A total of 367 lesions were visualized on MFBG as against 217 on MIBG. There were no MIBG-positive that were negative on MFBG. A median number of 11 (range 0-57) lesions per patient were detected on MFBG scan. Uptake was noted in osteomedullary only, (n=13), soft tissue only (n=1) and both soft tissue and osseous lesions (n=10). MFBG detected a median of 6 (range 1-24) additional lesions in 19 patients. In 16/19 patients where follow up was available, the discordance was related to true positive disease, including at least 116 sites. Respective median curie scores were 3 (range:0-22) and 9 (range:0-24) with MIBG and MFBG respectively. Conclusions: MFBG scan detected disease in all patients with MIBG positive disease. MFBG detected similar or more lesions compared to MIBG in patients with neuroblastoma, with overall increased scores. Further analysis to evaluate impact on patient management is underway. Clinical trial information: NCT02348749 .
A 5-hydroxymethylcytosine-based noninvasive model for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma: The METHOD-2 study.
Authors: Jianmin Xu, Wenju Chang, Baoqing Jia, Kefeng Ding, Zhizhong Pan, Wei Zhang, Guoqiang Su, Wei Zhang, Li Ren, Chuan He
Journal: Journal of Clinical Oncology (2023)

3042 Background: Detection of colorectal tumors at a time when there are more treatment options is associated with better outcomes. This prospective case-control study (NCT03676075) assessed the performance of 5-hydroxymethycytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) to detect advanced colorectal adenomas (ADA) or adenocarcinomas (CRC). Methods: This multi-center study enrolled 2,576 participants, including patients with newly diagnosed CRC (n=1,074), ADA (n=356), other solid tumors (n=80), and healthy individuals (HEA) (n=1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal, a highly sensitive chemical labeling approach. A weighted diagnostic model for CRC (stage I-III) and ADA was developed using the elastic net regularization in a training set of age-, sex-, region-matched samples and validated in independent samples. Results: Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. In an independent validation set of 482 samples, a 96-gene model trained in stage I-III CRC, ADA, and HEA achieved an AUC (area under the curve) of 92.6% (95% CI [confidence interval], 90.7-94.5%) for distinguishing CRC from HEA, regardless of primary location or mutation. This model also showed high capacity for distinguishing ADA from HEA with an AUC of 87.9% as well as cancer-type specificity. Model performance was further confirmed in samples from multiple centers. Functionally, differential 5hmC features associated with CRC and ADA demonstrated relevance to CRC biology, including pathways such as calcium and MAPK signaling. Conclusions: Genome-wide mapping of 5hmC in cfDNA shows promise as a highly sensitive and specific approach to be integrated in a screening program for improving early detection of CRC and high-risk ADA. Clinical trial information: NCT03676075 .
ctDNA-based genomic landscape analysis to evaluate molecular brake and gatekeeper mutations in FGFR2 alterations.
Authors: Paul Severson, Julia Sytnikova, Adithi Mohan, Nicole Zhang, Elifnur Yay Donderici, Richard Thomas Williams
Journal: Journal of Clinical Oncology (2023)

3049 Background: FGFR2 and FGFR3 (FGFR2/3) gene alterations are oncogenic drivers found across various cancer types and have been successful targets of drug development. Several FGFR inhibitors (FGFRi) are approved for clinical use, and most are ATP-competitive, reversible inhibitors (1 st -gen). Efficacy of the 1 st -gen FGFRi can be limited by acquired resistance mutations in the FGFR kinase domain, typically molecular brake or gatekeeper mutations, which disrupt compounds binding through conformational changes or through direct steric hindrance, respectively. Irreversible (covalent) FGFRi, such as futibatinib, are in development to overcome kinase domain resistance mutations. However, preclinical evidence indicates that some of the known resistance mutations (eg. V564L) remain insensitive to futibatinib. Methods: To assess the landscape of FGFR-driven cancers and to better understand the prevalence of molecular brake and gatekeeper mutations, we analyzed the distribution of FGFR2/3 alterations in a large clinical genomic research database. This ctDNA-based genomic database was selected for the analysis given that liquid biopsy is a fit-for-purpose method to detect acquired resistance mutations. Results: We identified over 2,100 patients with FGFR2/3 alterations. Non-small cell lung cancer (NSCLC), breast, bladder, and cholangiocarcinoma (CCA) had the highest number of patients with FGFR2/3 alterations. 36% of all FGFR2 alterations across all cancer indications consisted of molecular brake or gatekeeper mutations. This finding was most enriched in CCA and breast cancer where 51% and 57%, respectively, of FGFR2 alterations were molecular brake or gatekeeper mutations. In breast cancer patients, molecular brake mutations were common and represent activating mutations in FGFRi-naïve patients. A small number of FGFR3 gene fusions were detected in CCA patients who had significantly shorter time on 1 st -line treatment and trended toward shorter overall survival when compared to patients with FGFR2 fusions. We also identified CCA patients with FGFR2 fusions and one or more concurrent FGFR2 SNVs; primarily those in the kinase domain and associated with FGFRi resistance. Most of these putative cases of acquired resistance were polyclonal, with 2 or more (up to 8) FGFR2 SNVs coexisting with the fusion. Bladder cancer and NSCLC had the highest numbers of FGFR3 alterations. FGFR2/3 alterations were typically found without other driver mutations in CCA, bladder, and NSCLC patients. However, in breast there was a large overlap between FGFR2/3 alterations and other drivers. Conclusions: Herein, we identify a cohort of patients with FGFR2/3 molecular brake and gatekeeper mutations that may benefit from next-generation FGFR2/3-targeted therapies designed to inhibit a broad spectrum of both primary and secondary resistance mutations.
Deep learning-derived spatial organization features on histopathology images to predict prognosis in patients with colorectal liver metastasis, after hepatectomy.
Authors: Xin Wang, Yu-hong Li, Baocai Xing, Lin Qi, Jie-Ying Liang, Zhong-Wu Li, Shao-Yan Xi, Yu-Ni Lai, Feng Gao, De-Shen Wang, Ming-Tao Hu, Yi Cao, Xian-Rui Zhang, Li-Jian Xu, Ronald CK Chan
Journal: Journal of Clinical Oncology (2023)

3581 Background: Histopathological images of colorectal liver metastasis (CRLM) contain rich morphometric information that may predict patient outcomes, but current indicators depend on labor-intensive and subjective visual estimation. Herein, we aimed to develop an automated framework for tissue classification of routine H&amp;E stained whole-slide images and establish a risk-scoring model for better prognosis prediction in patients with CRLM. Methods: Using 161,371 hand-delineated image patches, we trained a robust deep convolutional neural network- CRLM-SPA for accurate classification of CRLM into seven tissue types. With the tissue classification results on two independent in-house cohorts (SYSUCC: n = 433, BJCH: n = 404), we systematically quantified spatial organization features (SOFs), involving whole-slide, tumor-infiltrating and tumor-distal SOFs for different tissue types as well as the interactions between tumor and non-tumor tissues. Subsequently, univariate Cox proportional hazards regression analysis was performed to investigate the association between various SOFs and patient outcomes. Nonredundant SOFs that are clinically relevant were selected to build a risk-scoring model for prognosis using multivariate Cox regression analysis in the SYSUCC cohort, followed by validation in the BJCH cohort. Results: CRLM-SPA achieved an overall classification accuracy of &gt; 93% in an independent set of 17,653 image patches. With the classification result, we calculated various SOFs and built a four-SOF risk-scoring model that significantly predicted overall survival (OS) in the discovery cohort, SYSUCC ( P = 1.40 10 -5 ; HR = 2.26; 95%CI: 1.55 - 3.29) and the independent validation cohort, BJCH ( P = 4.59 × 10 -4 ; HR = 2.00; 95%CI: 1.35 - 2.97). The prognostic performance of our SOF risk-scoring model is independent of the clinical risk score (CRS) system. Further stratification analyses in patients without preoperative chemotherapy (CTx) indicated that adjuvant CTx consistently improved OS in the SOF high-risk subgroups in both cohorts ( P = 0.018 and 0.049), but not in the SOF low-risk subgroups. Furthermore, a combined scoring system incorporating SOF and CRS considerably improved the prognostic performance in both cohorts over the individual SOF and CRS systems. Conclusions: CRLM-SPA showed a high accuracy in tissue classification and robustness in extracting prognostic information from H&amp;E images. The SOF risk-scoring system demonstrated a strong and robust prognostic value that is independent of CRS, and could therefore provide a time- and cost-efficient tool to assist clinical decision making for patients with CRLM.
Droplet digital PCR as an alternative method for detecting MET amplification in patients with non-small cell lung cancer.
Authors: Jun-wei Su, Cheng-Di Weng, Jin-Ji Yang
Journal: Journal of Clinical Oncology (2023)

e15107 Background: Mesenchymal-epithelial transition (MET) amplification is associated with resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer patients and poor prognosis. Fluorescence in situ hybridization (FISH) is the most commonly used method for detecting MET amplification but is not possible in cases where tissue samples are unavailable. Here, we evaluated the utility of droplet digital PCR (ddPCR) in detecting MET amplification in non-small cell lung cancer (NSCLC) patients. Methods: We evaluated a c-Met: EFTUD ddPCR assay of the c-Met gene and using EFTUD as the reference gene to determine c-Met amplification in plasma cfDNA samples from 80 advanced NSCLC patients. A total of 84 plasma samples were collected for MET amplification detection using ddPCR. Paired tissue samples using FISH were to evaluate the correlation between the MET-ddPCR ratio and MET FISH. Results were correlated with clinical findings. Results: We found that ddPCR had an 88.1% concordance rate with FISH in detecting MET CNG, with an area under the curve (AUC) of 0.84. Eleven patients were positive for MET amplification by FISH prior to MET inhibitor treatment, and these patients had a partial response rate (PR) of 45.5% and a median progression-free survival (PFS) of 12.1 months. However, MET amplification identified by ddPCR failed to distinguish significant clinical outcomes. The PR rate and median PFS for ddPCR-positive vs. negative patients were 57.1% vs. 50.0% and 12.1 months vs. 2.1 months (P = 0.276). Conclusions: Our results suggest that ddPCR is a reliable alternative to detect MET amplification in plasma cfDNA samples. Met status determined in cfDNA may have potential as a predictive factor for PFS after c-Met inhibitor therapy.
Characterization of visits to the emergency room by patients with colorectal cancer in the year prior to their diagnosis: A retrospective study.
Authors: Amir Massarweh, Baruch Brenner, Jonathan Ofer
Journal: Journal of Clinical Oncology (2023)

e15609 Background: Colorectal cancer (CRC) is one of the leading causes of cancer death globally, with more than 0.9 million deaths annually. Despite screening programs, many of the CRC patients (pts) are diagnosed at an advanced stage, resulting in an overall 5-year survival rate of only about 60%. Enhancing the detection of CRC in pts referred to the Emergency Room (ER) could potentially improve early detection and survival outcomes. While the prevalence of initial cancer diagnoses obtained through ER admission is documented, the proportion of individuals diagnosed with CRC who visited the ER during the year proceeding their diagnosis remains unknown. This study aimed to examine the percentage of CRC pts treated at Rabin Medical Center (RMC) who visited the ER in the year prior to diagnosis and to characterize these visits. Methods: A retrospective cohort study was conducted to identify pts diagnosed and treated at RMC for histologically confirmed CRC between 2012-2022 and to characterize their ER visits in the year prior to diagnosis. Each visit was recorded by date and the number of months before diagnosis. ER visits initiated for a recent diagnosis of CRC, i.e., occurring one month before diagnosis, were excluded. Demographic and clinical information (age at ER visit, gender, stage at diagnosis, number of visits, and interval between the first visit and diagnosis) was collected and analyzed. Results: Of the 2,240 pts treated for CRC at RMC between 2012-2022, 476 (21.2%) visited an ER, at RMC (13.3%) or elsewhere (7.9%), in the year prior to diagnosis. The median age at the first visit was 72 years (range: 25-96) and 55.7% were males. Pts were diagnosed with localized, locally advanced, and metastatic disease in 134 (45.0%), 70 (23.5%), and 63 (21.1%) cases, respectively, while stage was not yet established in 31 (10.4%). Quantitative and temporal characteristics of the ER visits are presented (Table 1). Pts had on average 1.6 visits (range: 1-11) in the year prior to diagnosis; 113 (37.9%) had 2 or more visits during that year. The median interval between the first ER visit and the CRC diagnosis was 4 months (range: 2-12); an interval of 5 months or longer was observed in 127 (42.6%) pts. Conclusions: To our knowledge, this is the first report on ER visits of CRC pts in the year prior to their diagnosis. The high percentage of pts visiting the ER highlights the importance of developing screening tools at the ER level to improve early detection and survival outcomes. This is further emphasized by prevalence of repeat ER visits and long interval between the first ER visit and the CRC diagnosis in many cases. [Table: see text]
Correlation of single-cell cytokine secretion with clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with capecitabine (C), bevacizumab (B), ± atezolizumab (A).
Authors: Niharika B. Mettu, Blake Waechter, Tyler J. Zemla, Yingmiao Liu, John C. Brady, Lynn Lin, Sacha Gnjatic, Kent J. Weinhold, Tanios S. Bekaii-Saab, Fang-Shu Ou, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2023)

3533 Background: The BACCI trial (NCT02873195) randomized 133 mCRC pts to C+B+A (investigational) or C+B+placebo. Longer progression free survival (PFS) was observed in the investigational vs placebo arm. To investigate T-cell functional heterogeneity, we performed single-cell proteomic analyses on pts with either long or short PFS and evaluated T-cell function as a prognostic and predictive biomarker. Methods: Isolated CD8+ and CD4+ cells were analyzed at baseline and first restaging from pts with long ( &gt; 6 mo, N = 14) or short ( &lt; 2 mo, N = 13) PFS. Single-cell, functional proteomic analyses were conducted using the IsoLight system (Isoplexis), which assessed secretion of 32 cytokines from an average of 786 cells per sample. The cumulative readout was polyfunctional strength index (PSI), a composite score of frequency and magnitude of secreted cytokines. Cytokines are organized into effector (E), stimulatory, chemoattractive (CA), regulatory, and inflammatory (I) clusters. Differential expression analyses were done using Wilcoxon rank-sum tests. Potential predictive effects were assessed using logistic regressions with interaction between treatment and biomarkers. No multiple comparison control was done due to the exploratory nature of analyses. Results: Baseline CD8+ and CD4+ cells were stimulated ex vivo and single-cell cytokine analyses performed. Prognostic analyses indicated that CD8+ cells from pts with long PFS had ~3-fold higher PSI compared to pts with short PFS (p = 0.005). Further analysis identified that the E (p = 0.005) and CA clusters (p = 0.005) most impacted PSI, significant individual cytokines are listed in the table. Baseline CD8+ cell function was not predictive of outcome. Baseline CD4+ cell function was not prognostic or predictive of outcome. Analysis of CD8+ cells after treatment identified that changes in CA cluster was prognostic of long PFS (p = 0.024). Cytokine changes from CD4+ cells were not prognostic; however, early changes in the CD4+ CA cluster were predictive of outcome (p-int = 0.055). Similarly, early changes in the CD8+ I cluster were predictive of outcome (p-int = 0.073). Conclusions: These results reveal pts with long PFS had more functional CD8+ T-cells with a higher PSI than pts with short PFS. Predictive analyses suggested that early changes in the CD4+ CA and CD8+ I clusters were associated with benefit from immunotherapy. These preliminary results highlight the importance of single-cell functional proteomic analyses. [Table: see text]
Safety and PK (pharmacokinetic) profile of niraparib (nir) + dostarlimab (dost) in pediatric patients (pts) with recurrent or refractory (RR) solid tumors: SCOOP study.
Authors: Francois Doz, Nicolas André, Pilar Guerra-García, Antonio Juan-Ribelles, Jaume Mora, Lucas Moreno, Nadège Corradini, Anne Huff, Courtney Nugent, Michele Snyder, Veronica Moroz, Danielle Wanik, Divya Gupta, Nidale Tarek, Alba Rubio-San-Simón
Journal: Journal of Clinical Oncology (2023)

10040 Background: Combination therapies may improve clinical outcomes in pediatric pts with tumors with single-agent resistance. Emerging preclinical and clinical data have shown a positive effect for combination PARP/immune checkpoint inhibition. The SCOOP study was designed to evaluate combination nir+dost in pediatric pts with non-central nervous system (CNS) RR solid tumors. Herein we present the safety, dose-limiting toxicities (DLTs), PK, and recommended phase 2 dose (RP2D) of nir+dost. Methods: SCOOP is a phase 1, multicenter, open-label, dose-escalation, and cohort-expansion study in pts aged ≥6 mo to &lt;18 y with non-CNS tumor types reported to have a BRCAness gene signature. Part 1A comprised multiple dose-level cohorts (0, 1A, 1B, and 2; Table) of pts ≥20 kg able to swallow nir tablets. The primary endpoint was determination of the RP2D of nir+dost based on DLT incidence during the first 2 cycles. Plasma concentrations were compared with simulated adult concentrations using population PK models. Results: A total of 23 pts with non-CNS RR solid tumors were enrolled with 16 evaluated for DLTs and 23 for PK analysis (see Table for dose-level cohorts and observed DLTs). Grade (Gr) ≥3 drug-related (DR) treatment-emergent adverse events (TEAEs) in part 1A included hematologic toxicities, decreased appetite, and fatigue, with DR serious TEAEs of immune-mediated encephalitis, headache, nausea, vomiting, cerebral hemorrhage, and hyponatremia. Observed plasma nir concentrations at 100 and 200 mg once daily (QD) in pediatric pts were similar to simulated adult concentrations at 200 or 300 mg QD. Observed dost concentrations at 7.5 mg/kg every 3 weeks (Q3W) in pediatric pts were in the expected range for adults at 500 mg Q3W. Conclusions: Observed DLTs were consistent with the individual safety profile of each drug; overall no unexpected safety issues were observed. Based on these results, nir 100 mg QD + dost 7.5 mg/kg Q3W was selected as the RP2D for the SCOOP expansion cohorts in neuroblastoma and osteosarcoma. Pts in the expansion study will receive nir+dost at the RP2D until disease progression. Clinical trial information: NCT04544995 . [Table: see text]